Cancers, among various diseases, have recently taken the first position of causes of death and there has been desired an earlier development and establishment of a novel therapy against cancers. In particular, there has been attempted a therapy against leukemia, a blood cancer, using agents having an inhibitory action on the proliferation of leukemia cells and an inducing action on the differentiation of the said cells. It is known that the differentiation induction of leukemia cells into mature leukocyte-like cells may inhibit the proliferation of leukemia cells, which leads to loss of properties of leukemia cells.
It is reported that the treatment with natural type of a retinoid, all-trans retinoic acid (hereinafter referred to as "ATRA"), brings complete remission in 90% or more of the patients suffering from acute promyelocytic leukemia with PML/RAR.alpha. transposition (New Eng. J. Med., Vol. 329, 177, 1993).
Recently, a retinoic acid receptor (hereinafter referred to as "RAR") has been found to be a receptor for ATRA (Nature, Vol. 330, 440, 1987 and ibid., Vol. 330, 624, 1987), and it is believed that ATRA would perform various transcriptional controls via RAR. However, relapses have frequently occurred in therapy using ATRA and, in the case of relapses after the treatment with ATRA, a re-remission rate by ATRA has been lowered to 36%. Moreover, ATRA may exhibit severe side effects and, when administered at a high dose, various disturbances have been induced in the skin, central nervous system, liver and so on. Furthermore, administration of ATRA to pregnant women would accompany a risk of teratogenesis. Accordingly, patients may have to face the problem to obviate those disturbances caused by a high dose. It is also known that continuous administration of ATRA induces binding proteins such as intracellular ATRA-binding protein (CRABP) and consequently a serum ATRA concentration may be reduced to eventuate in unfavorable results in view of the purpose of leukemia therapy (Blood, Vol. 82, 1949, 1993).
Recently, a new retinoid receptor, retinoid X receptor (hereinafter referred to as "RXR"), has been found and its ligand has been identified as 9-cis-RA which is a geometrical isomer of ATRA at the 9-position thereof (Cell, Vol. 68, 397, 1992). 9-cis-RA is known to be a strong ligand for not only RXR but also RAR, having a differentiation inducing activity in HL-60 cells of myelocytic leukemia cells ("IGAKU NO AYUMI", Vol. 175, 925, 1995 and Blood, Vol. 81, 1009, 1993).
However, 9-cis-RA is also known to be chemically unstable and easily isomerized to ATRA, from which similar side effects to those of ATRA may be expected. Thus, a possibly reduced dose of 9-cis RA has been desired.
On the other hand, VD.sub.3 known as an agent for improving bone metabolism has a cell differentiation inducing activity as ATRA does and induces the differentiation of those cells derived from colon cancer, breast cancer and leukemia (Endocrine Rev., Vol. 13, 765, 1992). Use of VD.sub.3 as an anticancer agent is also expected. However, VD.sub.3 is applicable only at a lower dose. For example, a serum VD.sub.3 concentration beyond 10.sup.-9 M may give rise to side effects such as hypercalcemia and others. Therefore, a clinical use of such a dose to cause a high VD.sub.3 concentration in the serum has been restricted (Cancer Treat. Rep., Vol. 69, 1399, 1985).
For combination of ATRA with VD.sub.3, Japanese Patent Kokai 7-2674 describes under the item of the prior art that a combined use of both compounds could produce only additive effect on the inhibition of growth and differentiation induction of HL-60 leukemia cells. The publication discloses a therapeutic agent for leukemia which comprises ATRA and a VD.sub.3 analogue in order to achieve a synergistic effect. However, it is apparent from Table 1 of the publication that a serum concentration of the VD.sub.3 analogue should be 10.sup.-8 M or more in order to accomplish 50% or more growth inhibition rate of leukemia cells. The use of VD.sub.3 at such a high concentration would produce possible side effects such as severe hypercalcemia as described above.
Our Japanese Patent Kokai 4-244076 discloses an esterified product of 9-cis-RA and a tocopherol derivative is useful for the treatment of skin ulcers, peptic ulcers and tumours. However, it does not disclose the ester is useful as a therapeutic agent for leukemia.
Under these circumstances, there has been desired a development of a novel and effective therapeutic agent for leukemia with less side effects on a living body, but a satisfactorily effective medicine has not yet been found out up to the present time. In view of this, there has been a need for a novel compound for use as a therapeutic agent for leukemia having a more potent therapeutic effect and a higher safety as compared with the prior art therapeutic agents for leukemia.